Our laboratory continues to develop realistic mathematical models of whole-body energy metabolism, macronutrient utilization, and the regulation of body weight and composition in both humans and rodents. Our computational framework integrates a variety of physiological data to construct the individual model components which are then integrated to compute the behavior of the entire system. The models use dietary carbohydrate, fat, and protein as model inputs to compute whole-body energy expenditure, substrate oxidation rates, de novo lipogenesis, gluconeogenesis, and the resulting changes in body weight and composition. The computational models are being used to study regulation of body weight and energy metabolism in the normal human and rodent, as well as alterations of metabolism that occur in conditions such as obesity, diabetes, and wasting syndromes like cachexia and anorexia. Continued development of our models is facilitating the investigation of various therapeutic interventions and their effects on metabolism, body weight and composition.